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Anesthesiology 2001; 95:2419 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Mechanism-based Pain Diagnosis

Issues for Analgesic Drug Development
Clifford J. Woolf, M.D., Ph.D.,* Mitchell B. Max, M.D.

ENORMOUS progress is currently being made by the diluting out the benefit in the subgroup with the tar-
exploitation of modern neurobiologic techniques in geted mechanism.
the elucidation of mechanisms that may contribute to In this review, we sketch a research agenda that might
the pathogenesis of pain.13 These indicate that pain can move us toward a mechanism-based analgesic develop-
be generated in multiple ways at a number of different ment. First, it is necessary to consider the following
sites that may coexist between and across diverse dis- questions: To what degree can clinicians directly assess
ease states.4,5 Molecular biologic techniques are contrib- pain mechanisms in patients? What is the evidence from
uting to the analysis of pain mechanisms and are leading controlled clinical trials that variation in analgesic re-
to the discovery of new targets, which are being used in sponse between patients can be explained by disease or
high throughput screens by the pharmaceutical industry syndrome, tissue of pain origin, or symptom-based as-
for the discovery of highly specific small molecules as sessment of pain mechanisms? How should analgesic
potential novel analgesics. The discovery of targets spe- development pathways be revised to most efficiently
cific to particular pain mechanisms will soon enable demonstrate the spectrum of efficacy of a new drug?
therapy to be targeted specifically at those mechanisms. What types of collaborations between academic pain
This raises several problems: how to identify the mech- researchers, industry, government research funders, and
anisms in an individual patient, how to test for the regulators can hasten the potential clinical benefits of
efficacy of a compound that may alter only one compo- mechanism-based pain treatment?
nent of a complex syndrome that involves multiple
mechanisms, and how to test for interaction between
two different compounds targeted at two independent Mechanism-based Pain Diagnosis
mechanisms. Clinical studies suggest that within conven-
tional diagnostic groups of chronic pain patients, there Pain is not a discrete sensory experience that is
are subgroups with differing responses to drug treat- switched on only by a particular or identifiable set of
ment,6 9 and yet the clinical development of new anal- pain stimuli acting on a unique or stable pain path-
gesic drugs has ignored this mechanistic heterogeneity. way to elicit an invariant sensation. Instead, pain is a
Trials that select patients based only on a disease may diverse set of complex perceptual events that are char-
produce a false-negative result, with the nonresponders acterized by their unpleasant or distressing nature. Al-
though, from our everyday experience, we tend to asso-
ciate pain only with an intense or noxious peripheral
stimulus, in most patients, pain arises either in the ap-
* Professor, Department of Anesthesia and Critical Care, Massachusetts Gen-
eral Hospital and Harvard Medical School. Senior Investigator, Pain and Neu- parent absence of any peripheral input (spontaneous
rosensory Mechanisms Branch, National Institute of Dental and Craniofacial pain) or in response to low-intensity or innocuous stim-
Research, National Institutes of Health, Bethesda, Maryland.
Received from the Department of Anesthesia and Critical Care, Massachusetts
uli that are usually not associated with pain (allodynia).
General Hospital and Harvard Medical School, Boston, Massachusetts. Submitted The induction of pain encompasses multiple different
for publication September 8, 2000. Accepted for publication January 9, 2001. neurobiologic components originating in a complex
Supported by grant No. NS 38253-01 from the National Institutes of Health,
Bethesda, Maryland (to Dr. Woolf). This article expresses the personal views of fashion from mechanisms that may manifest and interact
the authors and does not necessarily reflect those of the US Department of Health at many different levels of the neuraxis and that are
and Human Services. This article mentions several drugs in passing made by
companies for which Dr. Max has consulted, e.g., gabapentin and ketamine inherently dynamic or changeable. Although global out-
(Parke-Davis, now part of Pfizer, Ann Arbor, MI), lidocaine (Astra, now AstraZen- come measures such as a simple visual analog score or
eca, Wayne, PA), and fentanyl (Johnson & Johnson, Raritan, NJ). None of these
drugs is promoted here. Several specific drugs are mentioned in passing in the categorical scale may provide a crude integrated mea-
text of this article (lidocaine, ketamine, amitriptyline, gabapentin) as examples of sure of the total pain experienced by the patient, the
existing forms of analgesic therapy without any promotion for specific indica-
tions, as well as classes of drugs, such as COX-2 inhibitors. Dr. Woolf has acted mechanisms responsible for the pain, or possibly more
as a retained or ad hoc consultant to the following drug companies: Glaxo- important, the differential response of some mechanisms
Wellcome, Stevenage England (now GlaxoSmithKline), Bayer AG (Leverkusen,
Germany), Parke-Davis (Ann Arbor, MI; now Pfizer), Eli Lilly (Indianapolis, IN), and not others to a particular treatment, cannot be iden-
Pfizer (New York, NY), Searle (Chicago, IL; now Pharmacia), Roche Bioscience tified using these measures. That is not to say that the
(Palo Alto, CA), and Millenium Pharmaceuticals Inc. (Cambridge, MA).
Address reprint requests to Dr. Woolf: Department of Anesthesia and Critical
overall clinical aim should not be to relieve the global
Care, Massachusetts General Hospital and Harvard Medical School, 149 13th pain experience and its associated unpleasantness and
Street, Room 4310, Charlestown, Massachusetts 02129. Address electronic mail
to: Individual article reprints may be purchased
discomfort, but that a more rational way of achieving
through the Journal Web site, this may be to identify what mechanisms contribute,

Anesthesiology, V 95, No 1, Jul 2001 241


chain of sensory processing that lead to the experience

of a conscious awareness of pain? Until recently, a com-
mon view was that the pain system was a fixed label-line
system activated in the periphery only by nociceptors in
response to an adequate noxious stimulus. Although this
is true of nociceptive pain (pain evoked by a noxious
stimulus) in normal circumstances, it is certainly incor-
rect for pain hypersensitivity or spontaneous pain,
where a number of different input channels can lead to
the pain sensation, including (1) nociceptor activation in
the periphery by noxious mechanicalthermal or chem-
ical stimuli (nociceptive pain); (2) activation of sensi-
tized nociceptors in the periphery by low-intensity stim-
uli (peripheral sensitization); (3) ectopic discharge in
Fig. 1. A diagrammatic representation of the relation between nociceptors originating at a neuroma dorsal root gangli-
etiologic or disease factors, mechanisms, symptoms, and pain onperipheral nerve dorsal root (peripheral nerve inju-
syndromes. This relation holds both for pain syndromes in ry); (4) low-threshold afferent activation in the periphery
human patients and animal models of pain conditions. The
ideal for pain management is to treat the mechanisms (apart by low-intensity mechanicalthermal stimuli (in combina-
from disease-modifying therapy). The problem is how to iden- tion with central sensitization, synaptic reorganization, or
tify these mechanisms. At present, our only indication is the disinhibition); (5) ectopic discharge in low-threshold affer-
symptoms generated by the mechanisms, which, however, are
not equivalent to mechanisms. ents originating at a neuroma dorsal root ganglionperiph-
eral nerve dorsal root (peripheral nerve injury associated
target treatment specifically at these mechanisms, and with central sensitization, synaptic reorganization, or disin-
measure the effect of such treatment. hibition); and (6) spontaneous activity in central neurons
The major challenge in attempting any mechanism- (in the dorsal horn, thalamus, or cortex). It is important to
based assessment of pain is to identify in a particular try to identify the particular input channel responsible for
patient what mechanisms operate to produce the symp- generating a particular pain because this represents the first
toms experienced by the patient and then use this to anatomic target for treatment.
determine rational treatment (fig. 1). The conventional The pain evoked by different input channels repre-
approach has been to analyze patients on the basis of sents operation of multiple mechanisms: (1) activation of
common etiologies or diseases on the assumption that a high-threshold receptorion channel transducers in no-
single disease will operate to produce pain by single or ciceptor peripheral terminals (nociceptive transduc-
at least common mechanisms. This approach groups tion); (2) change in thresholdsensitivity of receptorion
patients into categories, such as post herpetic neuralgia, channel transducers in nociceptor peripheral terminals
postsurgical pain, or osteoarthritic pain. When a com- (peripheral sensitization); (3) changes in ion channel
mon disease is not easily identifiable, e.g., idiopathic low expressionphosphorylationaccumulation in primary
back pain, the patients tend to be classified on the basis afferents (altered sensory neuron excitability); (4) post-
of the anatomic referral pattern of the pain. Although translational changes in ligand- and voltage-gated ion
such an approach has utility, it ignores the possibility channel kinetics in central (spinal cord and brain) neu-
that a single etiologic factor may produce pain by diverse rons, changing their excitability and the strength of their
mechanisms, which may occur singly, sequentially, or synaptic inputs (central sensitization); (5) alterations in
together. Individual patients may have multiple mecha- the expression of receptorstransmittersion channels
nisms operating both serially (in a temporal sequence de- in peripheral and central neurons (phenotype modula-
pending on the natural history of the etiologic disease and tion); (6) modification of synaptic connections caused
the reaction of the nervous system to it) and in parallel. by cell death or sprouting (synaptic reorganization); and
How can we go about identifying pain mechanisms? A (7) loss of local inhibition at different relay levels in the
good starting point is to know what mechanisms can po- neuraxis and of descending inhibition originating in the
tentially produce pain. This is an area in which there have forebrain and brainstem and terminating in the brain-
been rapid advances over the past decade, although our stem and spinal cord, caused by decreased activation of
understanding still remains incomplete. neurons, downregulation of receptorstransmitters, and
cell death (disinhibition).
A considerable amount is known about the mecha-
Key Features of Pain Mechanisms nisms that operate in primary afferent and dorsal horn
neurons to produce pain. Much less is known about the
Different aspects of pain are likely to be mediated by changes that occur in the brain and how the effective,
different input channels. What input signals initiate the cognitive, and perceptual aspects of pain are generated.

Anesthesiology, V 95, No 1, Jul 2001


However, it is clear that the sensory cortex can undergo A mechanism-based approach to pain has implications
considerable plasticity in concert with the changes that for these steps at a number of levels. First, it will con-
occur in subcortical structures, and such supraspinal tribute to the development of valid hypotheses and
plasticity is likely to play a major role in shaping the pain therefore improve target selection. Second, it will assist
experience. the development and analysis of animal models suitable
Pain can be assessed at a number of different levels: to test the effect of any chemical lead on a particular
society (economic cost, effect on the family unit), the mechanism. Finally, it will assist the design of clinical
individual (personal suffering), the system (how the pain trials for evaluation of efficacy. For both animal models
is generated by the peripheral and central nervous sys- and clinical trials, the key concern needs to be how or if
tem), and cells and molecules (the particular change in one can infer the action of a particular drug on a given
the individual elements of the system that initiate and mechanism. In both cases, two key issues are selecting
maintain the pattern of functioning that expresses itself the patient populationanimal model that expresses the
as pain). Pain must be seen in the context of all of these mechanism and identifying what outcome measures can
different levels of expression if we are to truly under- be used to identify if the treatment has altered the pain
stand the mechanisms responsible. Although pain has an mechanism.
important psychological component, which needs to be
an element of any treatment strategy, this review con- Pain Mechanisms and Animal Models of Pain
centrates on pain as a sensory experience, because it is The imperative in developing laboratory animal mod-
here that rapid progress has been made in identifying els of pain has been to try to reproduce or mimic pain in
specific mechanisms. humans. To this end, a number of tests have been de-
vised to evaluate basal pain sensitivity, i.e., the reaction
of a normal or naive animal to graded-strength mechan-
Drug Development and Pain Mechanism ical, thermal, or chemical stimuli (nociceptive pain).
Beyond basal sensitivity, the aim has been to duplicate,
Drug development involves several key steps:
within strict ethical limits, clinical pain syndromes, no-
1. establishment of a biologic hypothesis of the mecha- tably, inflammatory pain and neuropathic pain. For in-
nisms involved in the pathophysiology of pain (e.g., flammatory pain, a wide range of inflammation-inducing
that prostaglandin E2 release from inflamed tissue agents and procedures have been applied to induce
contributes to the peripheral sensitization of cutaneous, soft tissue (including skin, subcutaneous tis-
nociceptors)10; sue, muscle, synovium), peritoneal, and visceral inflam-
2. identification of a potential molecular target based on mation to mimic sunburn, acute postsurgical pain, acute
the biologic hypothesis to screen for new analgesic soft tissue inflammation, monoarthritis, autoimmune
compounds (e.g., inhibition of the inducible enzyme polyarthritis, peritonitis, cystitis, colitis, and so on. For
cyclooxygenase COX-2 will prevent prostaglandin E2 neuropathic pain, the peripheral and central nervous
production)11; system have been damaged in a number of different
3. establishment of a screen to look for small molecules ways, including experimental diabetes, peripheral neu-
that bind with high affinity to the target (and, in the ritis, complete or partial nerve lesions, and spinal cord
case of COX-2, inhibit its action); injury. Attempts have also been made to model cancer
4. chemical optimization of any chemical hit to pro- pain by inducing experimental tumors. Most of these
duce a series of lead compounds that will interact models of pain rely on detecting a change in the thresh-
with high affinity with the target, but not others old or response to an applied stimulus (stimulus-evoked
(selectivity) that are not likely to be toxic, have bio- pain); there are very few reliable measures of spontane-
availability, or pharmacokinetic problems, which are ous pain, a major component of clinical pain.
economic to produce and can be protected by The criteria for a successful animal model, particularly
patents; from an industry perspective, have unfortunately been
5. test of the lead compound in animal models of pain to more ones of convenience and reliability than detection
confirm or refute the original hypothesis and evaluate of particular pain mechanisms. In many models, the end
for efficacy and potential side effects; point selected to test a drug action has been, for exam-
6. test of safety in humans and establish pharmacoki- ple, a change in the reaction to a warm stimulus whether
netic properties (in some cases, surrogate pain models applied by contact or radiant heat (heat hyperalgesia),
can be used to look at efficacy in volunteers; phase 1); because this is simple to perform and measure and en-
7. test of efficacy in small groups of patients (proof-of- ables a relatively high throughput drug testing program.
concept testing; phase 2); The data are then usually recorded as a positive or
8. performance of large-scale multicenter clinical trials negative result in a particular model without consider-
to assess efficacy and safety in a number of diverse ation of what actual mechanism the drug may be influ-
clinical conditions (phase 3). encing and without an explicit appreciation that each of

Anesthesiology, V 95, No 1, Jul 2001


the animal models is the expression of multiple mecha- ing, etc.; or (2) stimulus-evoked pain, or pain evoked in
nisms, each of which may need to be detected with response to mechanical, thermal (cold and heat), or
different outcome measures. Heat hyperalgesia is very chemical low- or high-intensity stimuli applied statically
rarely a clinical problem in humans, and the issue then is or dynamically to skin, joints, bone, muscle, or viscera.
whether a compound that acts on this end point in an A combination of studies using animal models and
animal model will have any useful clinical action in human investigations has identified some potential asso-
patients. The answer almost certainly is that if this is the ciations between particular mechanisms and particular
only action of the compound, if it leaves mechanical symptoms: (1) a reduction in the pain threshold to heat
sensitivity or spontaneous pain unaffected, it will have stimuli applied directly to a site of inflammation and
very limited utility except in a very small subpopulation peripheral sensitization; (2) tactile allodynia in a nonin-
of patients. The predictive value of any animal model flamed area and an N-methyl-D-aspartate (NMDA) recep-
resides then both in which mechanisms are involved and tormediated central sensitization; (3) spontaneous
what end points are measured. burning pain and C-fiber activity; and (4) paraesthesia
It is essential that animal models are viewed not as and ectopic A fiber activity.
models of human disease, as in most instances they are Although it is clear from available studies that particu-
actually different, but rather as tools to help dissect out lar mechanisms may be sufficient to elicit associated
the relative contribution of different pain mechanisms in symptoms, it is less clear whether they are always nec-
changing an animals behavior in a given situation. We essary. In other words, what confidence can we have
need ways of assessing if a drug acts via a particular that a given symptom reveals the presence of a defined
mechanism involved in the generation of pain. The end mechanism? The answer at the moment is that we know
of the preclinical drug development program should too little of the numerous mechanisms that may poten-
provide information on whether the drug has an action tially produce pain and even less about their coupling
on basal pain sensitivity or the altered sensitivity present with individual symptoms. Although tactile allodynia
in inflammatory, cancer, and neuropathic models, if it may reflect central sensitization, it is conceivable that it
acts on nociceptor terminals to block transduction, on may also result from central disinhibition and a sprouting
axons to block conduction, or in the central nervous of low-threshold afferent terminals in the dorsal horn.
system to modify transmission. To do this, multiple mod- Nevertheless, in the absence of other diagnostic ap-
els with a number of different end points should be used proaches, it is important for clinical trials to be designed
in a matrix fashion. There is also limited information on to collect as much information as possible about symp-
how well a compound should be expected to perform in tom clusters and their differential expression and re-
animal models before it should be selected for study in sponsiveness to specific highly targeted treatment (fig.
patients. Do you need a 100% reversal or is 50% good 1). It needs to be recognized, however, that different
enough? Because nonlocomotor central nervous system pain mechanisms are not independent and that even
side effects (nausea, dizziness) are difficult to detect, a highly targeted treatment may alter multiple outputs. A
greater efficacy may be demonstrable in animals than in decrease in ectopic activity in primary sensory neurons
humans, where such side effects will often limit the produced by a specific sodium channel blocker, for
maximum dose tolerated. example, may directly decrease spontaneous pain but
may also reduce the secondary tactile allodynia that
results from the central sensitization in the spinal cord
Difficulties of Identifying Precise Pain activated by the ectopic input. Furthermore, drugs that
Mechanisms in Humans act on different molecular targets may produce similar
outcomes in terms of symptoms. A sensory neuron-spe-
At present there is broad agreement among pain clini- cific sodium channel blocker and a drug that acts on the
cians and basic scientists that no diagnostic tools are presynaptic terminal of primary afferents to block trans-
available to unambiguously identify which mechanisms mitter release may both reduce spontaneous pain.
are present in a given patient, never mind which molec-
ular targets are responsible. The only option we have at
Have Distinctions among Pain Symptoms or
the moment is to analyze patients on the basis of symp-
Pharmacologic, Tissue, or Disease Diagnoses
tom clusters rather than just on disease (fig. 1). The
Explained Differences in Response to
assumption here is that common mechanisms initiated
by diverse etiologic factors may elicit common pain
symptoms. Patients grouped on the basis of shared symp- Symptoms as an Indicator of Mechanism
toms may include the following categories: (1) sponta- Clinical investigators have tried for two decades to find
neous pain, which may be continuous or intermittent, different responses of symptoms in analgesic drug trials,
superficial or deep, and which may elicit different sub- particularly in studies of chronic neuropathic pain. To
jective sensations described as burning, shock-like, ach- our knowledge, the single success to date has been the

Anesthesiology, V 95, No 1, Jul 2001


demonstration that postherpetic neuralgia patients with success in using drugs themselves as a probe of mecha-
allodynia and no sensory loss respond to topical anes- nism. In small groups of patients, pain relief after a brief
thetics, whereas patients with major sensory loss do infusion of opioid8 or lidocaine28 has predicted subse-
not.9 Studies of opioids,12 tricyclic antidepressants,1214 quent response to long-term treatment with opioid or
clonidine,7 and gabapentin15 in neuropathic pain have mexiletine. Although clinicians have used other types of
failed to identify characteristics of patients or pain symp- drug infusions as diagnostic tests to guide therapy, e.g.,
toms more likely to respond to treatment. Steady and intravenous phentolamine or epidural opioid, in most
paroxysmal pain, allodynia, and pain of various other reports long-term treatment has been limited to respond-
qualities tended to be reduced in parallel, and quantita- ers to the infusion, which precludes validation of the
tive sensory testing has not been illuminating,16,17 al- infusion as a predictive test. In other clinical trials, drugs
though this may reflect the insensitivity or inappropri- with selective actions have benefited too small a subset
ateness of the outcome measures used. to yield a statistically significant result, but a second
Recent clinical trials in postoperative patients suggest study of apparent responders, an enriched enrollment
that it may be informative to separately assess pain at rest study,7,29,30 has confirmed that the subset responds con-
and several types of evoked pains. Stubhaug et al.18 sistently on repeated drug challenges.
reported that very-low-dose ketamine infusion reduces Drug challenges have a potential advantage over sen-
the area and intensity of mechanical hyperalgesia around sory tests in that there are probably many more ways to
a nephrectomy incision through day 7, although it had stimulate or block sites of pain processing with selective
little effect on overall pain after the first postoperative drugs than with bedside examining tools. There are also
day. In postoperative dental pain, the -amino-3-hy- limitations. A brief period of drug testing in the clinic
droxy-5-methyl-4-isoxazoleproprionic acid (AMPA) kain- may sometimes fail to predict how the patient will feel
ate glutamate receptor antagonist LY 293558 has mini- during the activities of daily life most limited by pain.8
mal effects on resting pain but has a robust effect on pain Repeated exposures to drug make patients familiar with
evoked by mouth opening.19 Movement-evoked postop- its side effects and increase the chance of active pla-
erative pain is more resistant than rest pain to the effects cebo effects.31
of either local anesthesia of the surgical wound or intra- We suggest that regulators encourage the use of en-
venous fentanyl.20,21 Because movement-evoked pain riched enrollment studies in the development of treat-
limits rehabilitative efforts and everyday activities, a drug ments for chronic pain, including the possibility of ac-
that disproportionately blocks movement-evoked pain cepting such data as evidence for efficacy when studies
would be potentially valuable but might be dropped in broader populations are inconclusive. Of course, this
early in development after negative acute pain studies will require greater attention to the methods for such
that assessed only pain at rest. The traditional way of studies. For example, we must learn more about how
conducting postoperative pain studies is to let the study much analgesia might be produced if patients are un-
nurse choose either a resting state or pain-provoking blinded by side effects, and what steps (active placebos,
maneuver to adjust baseline pain to a moderate-to-severe standard analgesic comparisons, blinding question-
level,22 a method that makes it impossible to infer the naires) could minimize the chance of false-positive
mechanism of the pain. results.
Adoption of multiple evoked pain measures will re-
quire work to standardize and validate the methods. Tissue Diagnosis as a Correlate of Pain Mechanism
Even in postoperative dental pain, the most common Tissue type may provide a clue to mechanism because
screening model for new analgesics, little work has been innervation pattern, mix of neurotransmitters, and cen-
performed on evoked pain. These measures might in- tral processing may differ among tissue types. This seems
clude pain evoked by standardized movement and static most compelling for pain resulting from damage to the
and dynamic mechanical stimuli.23 Electrical stimuli near nervous system, in which there are anatomic changes,
the wound can selectively activate A- fibers even in the such as sprouts from injured nerves, not seen in other
presence of sensitized C nociceptors.24,25 Administra- persistent pain types. Galer et al.6 found that 58% of
tion of stimuli closely spaced in time can test for wind-up patients with a variety of peripheral nerve lesions re-
of pain.26 Woolf and Decosterd27 suggested a list of pain ported excellent relief from a lidocaine infusion, com-
symptoms that could be quickly assessed in a brief eval- pared with 21% of patients with lesions of other tissues.
uation, but its utility or sensitivity for identifying differ- Tricyclic antidepressant drugs reduced pain in approxi-
ent evoked pain clusters needs to be validated. mately 20 controlled clinical trials in patients with dia-
betic and other neuropathies, postherpetic neuralgia,
Pharmacologic Diagnosis of Pain Mechanism and postmastectomy pain14,32 but have shown inconsis-
Although the ideal of pain researchers has been to tent effects in conditions of other tissues, including ar-
infer mechanism from a sensory test and then choose thritis and idiopathic low back pain.33,34
drug treatment accordingly, there has been a bit more Although basic scientists have claimed that pain pro-

Anesthesiology, V 95, No 1, Jul 2001


cessing in viscera may differ from other tissues (e.g., question of whether results in the postoperative dental
transmission via dorsal column postsynaptic pathways35 model predict usefulness in many of the most common
or response to peripheral opioids36), there are too few chronic pain conditions.
clinical trials in visceral pain to examine tissue-related
differences in analgesic response in humans. Neverthe-
less, there are indications that central sensitization may Direct Comparisons of Analgesics Are
contribute to a secondary pain hypersensitivity in the Essential for Clinical Decisions
gastrointestinal tract in a way that resembles secondary
hyperalgesia in the skin.37 Migraine, which may arise Mechanism-based diagnosis, whether based on symp-
from afferent input from cerebral blood vessels and dura, toms, drug challenge, disease, or tissue, will better assist
has a sensitivity to drugs (the triptan 5-hydroxytrypta- treatment if these criteria can be examined in studies
mine 1DE agonists) that are ineffective for other acute that compare several different classes of analgesics.
pains, implying a unique role for this receptor subtype in Granting agencies and regulatory guidelines should pro-
the pathogenesis of this particular pain, but it does mote these types of comparisons, even when the com-
respond to nonsteroidal antiinflammatory drugs and opi- parator has not been approved for pain indications (e.g.,
oids, which have action on most nonneuropathic pains. tricyclic antidepressants or gabapentin).

Disease Diagnosis as a Correlate of Pain

Mechanism Testing Multiple Predictors of Response Will
Although traditional disease or syndrome diagnoses Require Large Sample Sizes and
certainly encompass a mix of pain mechanisms, the Improvements in Study Efficiency
differing tissue changes and time course in each diagno-
sis may make the mix of pain mechanisms different It is likely that clinical researchers will identify some
between disease groups. For example, although diabetic treatments that produce powerful and selective effects
neuropathy and postherpetic neuralgia have resembled in some mechanistic subgroups, much like carbamaz-
each other in their responses to tricyclic antidepressants epine appears to have a particularly robust effect in
and gabapentin, studies with the NMDA glutamate re- classic trigeminal neuralgia. For many other analgesic
ceptor antagonist dextrometherphan38 have shown re- agents, however, differences in response between diag-
sponse in diabetics but not postherpetics. Compared nostic groups or between treatments will be small be-
with diabetic neuropathy, pain in human immunodefi- cause of overlapping sets of mechanisms. Large sample
ciency virusrelated neuropathy has appeared to be rel- sizes will be needed to show these differences, because
atively resistant to amitriptyline39,40 but sensitive to sample size quadruples when one halves the size of the
nerve growth factor.41 Although some researchers have treatment difference one wishes to detect. Moreover, we
suggested that combining patients with mechanical allo- have suggested that investigators examine many differ-
dynia across diagnostic groups would be a step toward ent clinical featuressymptoms, sensory examination,
mechanism-based diagnosis, it might even be more dif- drug response, disease, and tissue type on drug re-
ficult to detect an effect in the combined group. As sponse. The many simultaneous diagnostic groups being
previously discussed, multiple mechanisms can give rise examined will also inflate the number of false-positive
to allodynia, and different diagnostic groups might have results occurring by chance. A convincing result will
different mixes of mechanisms. require even further increases of sample size or equiva-
Another example of disease diagnosis making a differ- lent decreases in the variance. The large sample sizes
ence within a tissue category is the contrast in drug will require multicenter trials (in which sophisticated
response between muscle strains and fibromyalgia. Muscle quantitative sensory testing will be impractical) and put
strains respond to the same antiinflammatory drugs, as do a premium on methodologic improvements to decrease
postoperative pain conditions. Fibromyalgia does not re- the variance. Crossover trials, for example, appear to
spond to antiinflammatory drugs42 but, unlike postopera- offer equivalent power to parallel-group studies that re-
tive pain, is sensitive to tricyclic antidepressants.43 cruit 510 times the number of patients.45 Regulatory
A major obstacle to understanding the correlation of agencies have been reluctant to accept data from cross-
disease and tissue diagnosis with analgesic response is over studies because they like to see a large number of
the virtual confinement of analgesic clinical trials to a patients treated anyway, and because statisticians criti-
few diseases, postoperative pain, neuropathic pain, cized some crossover designs (particularly the two-pe-
headache, facial pain, arthritis, and cancer.44 With their riod, two-treatment design) for vulnerability to carryover
eyes on short-term costs and returns, industry scientists effects. Some statisticians consider these technical prob-
are reluctant to conduct clinical trials in a condition until lems to be overstated,46 but even if regulatory agencies
academic investigators have demonstrated their feasibil- continue to use only first-period data for pivotal demon-
ity. For this reason, we cannot yet answer the simple stration of efficacy, they should encourage the use of

Anesthesiology, V 95, No 1, Jul 2001


data from crossover periods to provide clues to individ- receptor antagonists. VR-1 receptor agonists and antag-
ualizing treatment and comparing therapies. onists may be used to dissect the contribution of sub-
In addition, pain researchers must take up the rarely populations of peripheral receptors and changes in their
addressed issue of which pain assessment techniques are transduction. SNS or type III selective Na channel
most efficient in detecting treatment differences in blockers, glutamate receptor subunitspecific antago-
chronic pain studies.47 Small improvements in method nists, opiate receptor agonists, and adenosine subtype
could provide great gains. For example, Jensen and Mc- selective agonists may also prove to be as important for
Farland48 suggested that averaging 714 diary ratings of diagnosis as for therapy.
pain over 1 week instead of using a single rating might Functional brain imaging may contribute to mechanis-
eliminate as much as half the variance, an improvement tic inferences in intensive research settings, particularly
equivalent to doubling the sample size. if resolution improves enough to image small areas of the
spinal cord and brainstem. Functional magnetic reso-
nance and new positron emission tomography tech-
Clinical Trial Data Describing Patient-by- niques make possible single-patient studies of the spatial
Patient Diagnostic Features and Responses of and temporal patterns of functional change. Within a
Symptoms Must Be Made Widely Available few years, knowledge of functionally significant poly-
morphisms in most human genes may facilitate new
Many published analgesic trial reports often focus on
mechanistic distinctions within pain syndromes and
mean outcomes of global pain rating scales. For exam-
help clinicians tailor treatments to address the abnormal-
ple, two recent reports of large placebo-controlled stud-
ity in function.
ies of gabapentin in diabetic neuropathy15 and posther-
petic neuralgia49 showed statistically significant effects
on overall pain and quality of life, but said nothing about Need for Collaboration among Research
response of the individual pain qualities that had been Sectors
collected with tools such as the Short-Form McGill Pain
Questionnaire or physical examination characteristics A rational approach to mechanism-based treatment
such as allodynia. will require the validation of new assessment tools and
Investigators who discern patterns of response accord- diagnostic techniques, extension of pain research into
ing to symptom or tissue or pharmacologic diagnosis in the full range of common clinical pain conditions, and
their own studies need to be able to reexamine individ- the collection and cross-analysis of data from large clin-
ual patient data in other studies to confirm their hypoth- ical trials. This is beyond the capacities of any sector of
eses. However, even when investigators submit such pain researchers. Academic researchers have the long-
large tables for publication, space limitation often makes term perspective to explore underworked pain condi-
this impossible. We propose that mechanisms be devel- tions and validate new tools, but their corresponding
oped to encourage routine submission of detailed single- government research agencies fund few large analgesic
patient data and its storage in an easily accessed form trials. Industry already funds large trials but tends to
such as a web site. want a shorter-term payoff and is leery of untested pain
models or methods. Regulatory scientists often have
seen the most data from new compounds and under-
Can Tests of Clinical Pain Mechanisms Keep stand current research pitfalls but rarely have time or
Up with Basic Science Insights? funding for research. Therefore, we propose a novel
coordinated effort among these groups.
Although pain clinicians have dreamed of being able to
examine a patient and infer pain mechanisms, the ability
of neurobiologists to dissect pain mechanisms in animals Recommendations
has created more possibilities than the clinician can
We recommend joint planning among research sec-
currently distinguish using a standard history, a safety
tors. We encourage biomedical research funding agen-
pin, von Frey hair, and thermal probe. Even with an
cies, drug regulatory agencies, industry, and academic
expansion of the number of clinical researchers, this
scientists to develop novel collaborative mechanisms to
trend will probably continue. The most specific tools
hasten the impact of basic mechanistic insights on pain
clinical researchers will have to dissect out pain mech-
treatment and to that ensure lines of communication
anisms will be the new target- or mechanism-selective
between basic scientists and clinicians are improved.
drugs. These would be used in combination with a more
Biomedical research funding agencies should encour-
sophisticated history designed to elicit more information
age research in the following areas:
about possible mechanism and sensory or neurophysio-
logic tests.27 For example, the importance of central 1. comparison of data from animal models and clinical
sensitization might be assessed by response to NMDA trials to optimize mechanism-based coordination be-

Anesthesiology, V 95, No 1, Jul 2001


tween these two components of analgesic community in a manner that would not damage their
development; competitive position. The professional pain-related orga-
2. development of more efficient methods for repeated- nizations and their journals should encourage investiga-
dose analgesic clinical trials, e.g., determining which tors submitting manuscripts to include tables of patient-
types of scales minimize variance; by-patient data, including diagnostic features and
3. development of valid assessment methods for multi- response of distinct pain symptoms. In cases where this
ple pain-related symptoms for large clinical trials, is too lengthy for print publication, an accessible web
including pain qualities, and activity-evoked pain; site should be provided.
4. new tests to diagnose pain mechanisms, particularly In conclusion, based on an analysis of the potential
those that can be extended to large multicenter clin- utility of a mechanism-based approach to pain diagnosis,
ical trials; we make recommendations for a new concerted effort
5. the strengths and weaknesses of short-term drug in- by academics, the pharmaceutical industry, and drug
fusions as predictors of responses to chronic therapy; regulatory bodies to jointly introduce new tools to assess
6. development of clinical analgesic trials in common pain, validate these tools, and use them to improve the
conditions rarely included in current research, partic- sensitivity and value of clinical pain trials.
ularly visceral pain syndromes related to the gastro-
intestinal, urinary, and reproductive organs and the The authors thank Ian Gilron, M.D., M.Sc., F.R.C.P. (Assistant Professor, De-
partment of Anaesthesia, Queens University, Kingston, Ontario, Canada), and
heart; after groups of these patients are developed, a Isabelle Decosterd, M.D. (Chef de Clinique, Anesthesiology Department, Centre
government-funded group of academic pain research- Hospitalier Universitaire Vaudois, Lausanne, Switzerland), for reviewing the
ers might choose new compounds with interesting
mechanisms to study in these populations, as a sub-
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